Silencing Mediator of Retinoid and Thyroid Hormone Receptors (SMRT)—A Link between Adipocytes, Inflammation, and Glucose Intolerance

Silencing Mediator of Retinoid and Thyroid Hormone Receptors (SMRT) is a nuclear corepressor, which regulates the transcriptional activity of metabolically essential transcription factors. While SMRT has been shown to modulate adipocyte function, in vivo experiments utilizing knock-out (KO) models have led to conflicting results. To more rigorously define the role of SMRT in the adipocyte, we generated adipocyte-specific SMRT KO (adSMRT KO) mice by crossing adiponectin-Cre mice with floxed SMRT mice on a C57/BL6 background. When adSMRT KO mice are challenged with a 45% high-fat diet, we observe 20% increase in glucose intolerance (p=0.006) compared to wild type (WT) counterparts. Additionally, RNA-Seq data of adipose tissue from these mice indicate a dramatic up-regulation of inflammatory gene expression. To further characterize the pro-inflammatory phenotype, we utilized flow cytometry to identify infiltration of specific populations of adipose tissue inflammatory cells. We found that overall macrophage infiltration in the adipose tissue of KO mice increased two-fold (p=0.026), with anti-inflammatory M2 macrophages infiltrating in significantly lower proportions (p=0.017), indicating a higher ratio of M1:M2 cells in the KO mice compared to WT. In contrast, body weight and total fat mass were not altered. These data suggest a role for SMRT in the cross-talk between adipocytes and pro-inflammatory macrophages for the regulation of systemic glucose tolerance, distinct from the development of obesity. SMRT therefore integrates metabolic and inflammatory signals to maintain physiological homeostasis.